Regulation of wound healing and organ fibrosis by toll-like receptors

Huebener, Peter; Schwabe, Robert F.

doi:10.1016/j.bbadis.2012.11.017

Cited by 125 publications

(106 citation statements)

References 227 publications

(229 reference statements)

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“…Chronic liver diseases are associated with enhanced portal inflow of gut-derived microbiota products [lipopolysaccharide (LPS), bacterial DNA, peptidoglycan, viral and fungal components host DNA], due to increased intestinal permeability (29). Several studies have reported the beneficial impact of intestinal decontamination by antibiotics on liver fibrogenesis, suggesting that gut microbiota enhances liver fibrogenesis (79).…”

Section: Immunoregulationmentioning

confidence: 99%

“…The identification of Toll-like receptors (TLRs) in HSCs has uncovered the major contribution of gut-derived bacterial products in the inflammatory reaction underlying progression of fibrosis (29). Chronic liver diseases are associated with enhanced portal inflow of gut-derived microbiota products [lipopolysaccharide (LPS), bacterial DNA, peptidoglycan, viral and fungal components host DNA], due to increased intestinal permeability (29).…”

Section: Immunoregulationmentioning

confidence: 99%

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Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

Mallat

Lotersztajn

2013

American Journal of Physiology-Cell Physiology

196

220

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Liver fibrosis is the common scarring reaction associated with chronic liver injury that results from prolonged parenchymal cell injury and/or inflammation. The fibrogenic response is characterized by progressive accumulation of extracellular matrix components enriched in fibrillar collagens and a failure of matrix turnover. This process is driven by a heterogeneous population of hepatic myofibroblasts, which mainly derive from hepatic stellate cells and portal fibroblasts. Regression of fibrosis can be achieved by the successful control of chronic liver injury, owing to termination of the fibrogenic reaction following clearance of hepatic myofibroblasts and restoration of fibrolytic pathways. Understanding of the complex network underlying liver fibrogenesis has allowed the identification of a large number of antifibrotic targets, but no antifibrotic drug has as yet been approved. This review will highlight recent advances regarding the mechanisms that regulate liver fibrogenesis and fibrosis regression, with special focus on novel signaling pathways and the role of inflammatory cells. Translation of these findings to therapies will require continued efforts to develop multitarget therapeutic approaches that will improve the grim prognosis of liver cirrhosis.

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Section: Immunoregulationmentioning

confidence: 99%

Section: Immunoregulationmentioning

confidence: 99%

Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

Mallat

Lotersztajn

2013

American Journal of Physiology-Cell Physiology

196

220

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“…Necrotic cell supernatants were prepared from mouse tubular cells by repeated freezing and thawing. BMDCs were stimulated with necrotic supernatant with different concentration (50,150, and 250 ml) as well as AhR agonist (FICZ; Enzo Life Sciences) and H 2 O 2 (Merck). We purchased ultrapure LPS (from Escherichia coli strain K12), pI:C RNA, Pam3Cys, imiquimod, and CpG (InvivoGen).…”

Section: Bmdc Stimulation Experimentsmentioning

confidence: 99%

Toll-Like Receptor 4–Induced IL-22 Accelerates Kidney Regeneration

Kulkarni

Hartter

Mulay

et al. 2014

Journal of the American Society of Nephrology

126

127

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AKI involves early Toll-like receptor (TLR)-driven immunopathology, and resolution of inflammation is needed for rapid regeneration of injured tubule cells. Notably, activation of TLRs also has been implicated in epithelial repair. We hypothesized that TLR signaling drives tubule regeneration after acute injury through the induction of certain ILs. Systematic screening in vitro identified IL-22 as a candidate proregeneratory factor in primary tubular cell recovery, and IL-22 deficiency or IL-22 blockade impaired postischemic tubular recovery after AKI in mice. Interstitial mononuclear cells, such as dendritic cells and macrophages, were the predominant source of IL-22 secretion, whereas IL-22 receptor was expressed by tubular epithelial cells exclusively. Depleting IL-22-producing cells during the healing phase impaired epithelial recovery, which could be rescued entirely by reconstituting mice with IL-22. In vitro, necrotic tubular cells and oxidative stress induced IL-22 secretion selectively through TLR4. Although TLR4 blockade during the early injury phase prevented tubular necrosis and AKI, TLR4 blockade during the healing phase suppressed IL-22 production and impaired kidney regeneration. Taken together, these results suggest that necrotic cell-derived TLR4 agonists activate intrarenal mononuclear cells to secrete IL-22, which accelerates tubular regeneration and recovery in AKI.

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“…In addition to PDGF and TGF-β, a number of other mediators such as angiotensin II, endothelin-1, chemokines, leptin, interleukin-4 (IL-4), IL-6 and IL-13 play vital roles in fibrogenesis (13). Despite their protuberant role in fibrogenesis, recent studies indicate Toll-like receptors (TLRs), a group of receptors that regulate innate and adaptive immune responses, as significant modulators of inflammation during fibrosis (14)(15)(16). TLRs recognize pathogen-associated molecular patterns (PAMPs) and activate innate and adaptive immune responses to confiscate pathogens.…”

Section: Cellular Crosstalk Mechanism Of Toll-like Receptors In Gingimentioning

confidence: 99%

Cellular crosstalk mechanism of Toll-like receptors in gingival overgrowth (Review)

Subramani

Rathnavelu

Alitheen

2015

International Journal of Molecular Medicine

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Abstract. Gingival overgrowth is an undesirable outcome of systemic medication and is evidenced by the accretion of collagenous components in gingival connective tissues along with diverse degrees of inflammation. Phenytoin therapy has been found to induce the most fibrotic lesions in gingiva, cyclosporine caused the least fibrotic lesions, and nifedipine induced intermediate fibrosis in drug-induced gingival overgrowth. In drug-induced gingival overgrowth, efficient oral hygiene is compromised and has negative consequences for the systemic health of the patients. Toll-like receptors (TLRs) are involved in the effective recognition of microbial agents and play a vital role in innate immunity and inflammatory signaling responses. TLRs stimulate fibrosis and tissue repairs in several settings, although with evident differences between organs. In particular, TLRs exert a distinct effect on fibrosis in organs with greater exposure to TLR ligands, such as the gingiva. Cumulative evidence from diverse sources suggested that TLRs can affect gingival overgrowth in several ways. Numerous studies have demonstrated the expression of TLRs in gingival tissues and suggested its potential role in gingival inflammation, cell proliferation and synthesis of the extracellular matrix which is crucial to the development of gingival overgrowth. In the present review, we assessed the role of TLRs on individual cell populations in gingival tissues that contribute to the progression of gingival inflammation, and the involvement of TLRs in the development of gingival overgrowth. These observations suggest that TLRs provide new insight into the connection among infection, inflammation, drugs and gingival fibrosis, and are therefore efficient therapeutic target molecules. We hypothesize that TLRs are critical for the development and progression of gingival overgrowth, and thus blocking TLR expression may serve as a novel target for antifibrotic therapy.

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Regulation of wound healing and organ fibrosis by toll-like receptors

Cited by 125 publications

References 227 publications

Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

Toll-Like Receptor 4–Induced IL-22 Accelerates Kidney Regeneration

Cellular crosstalk mechanism of Toll-like receptors in gingival overgrowth (Review)

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